Facile Generation of Heterotelechelic Poly(2‐oxazoline)s Towards Accelerated Exploration of Poly(2‐oxazoline)‐based Nanomedicine

Controlling the end‐groups of biocompatible polymers is crucial for enabling polymer‐based therapeutics and nanomedicine. Typically, end‐group diversification is a challenging and time‐consuming endeavor, especially for polymers pre‐pared via ionic polymerization mechanisms with limited functional group tolerance. In this study, we present a facile end‐group diversification approach for poly(2‐oxazoline)s (POx), enabling quick and reliable production of hetero‐telechelic polymers to facilitate POxylation. The approach relies on the careful tuning of reaction parameters to establish differential reactivity of a pentafluorobenzyl initiator fragment and the living oxazolinium chain‐end, allowing the selective introduction of N‐, S‐, O‐nucleophiles via the termination of the polymerization, and a consecutive nucleophilic para‐fluoro substitution. The value of this approach for the accelerated development of nanomedicine is demonstrated through the synthesis of well‐defined lipid‐polymer conjugates and POx‐polypeptide block‐copolymers, which are well‐suited for drug and gene delivery. Furthermore, we investigated the application of a lipid‐POx conjugate for the formulation and delivery of mRNA‐loaded lipid nanoparticles for immunization against the SARS‐COV‐2 virus, underscoring the value of POx as a biocompatible polymer platform.